EP0691422B1 - Process for the preparation of substituted diaminodicarboxylic acid derivatives - Google Patents
Process for the preparation of substituted diaminodicarboxylic acid derivatives Download PDFInfo
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- EP0691422B1 EP0691422B1 EP95109588A EP95109588A EP0691422B1 EP 0691422 B1 EP0691422 B1 EP 0691422B1 EP 95109588 A EP95109588 A EP 95109588A EP 95109588 A EP95109588 A EP 95109588A EP 0691422 B1 EP0691422 B1 EP 0691422B1
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- 239000002253 acid Substances 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 5
- -1 9-fluorenylmethyl Chemical group 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000005868 electrolysis reaction Methods 0.000 claims abstract description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 8
- 238000006612 Kolbe reaction Methods 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 5
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract 3
- 125000004122 cyclic group Chemical group 0.000 abstract 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 0 CC(C(*)=O)N* Chemical compound CC(C(*)=O)N* 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KOUREPLKQLUSFY-ZETCQYMHSA-N (2s)-2-(butoxycarbonylamino)pentanedioic acid Chemical compound CCCCOC(=O)N[C@H](C(O)=O)CCC(O)=O KOUREPLKQLUSFY-ZETCQYMHSA-N 0.000 description 1
- YQZHANAPVDIEHA-UHFFFAOYSA-N 2,7-bis(azaniumyl)octanedioate Chemical compound OC(=O)C(N)CCCCC(N)C(O)=O YQZHANAPVDIEHA-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000006576 Kolbe electrolysis reaction Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 238000000160 carbon, hydrogen and nitrogen elemental analysis Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004130 chiral capillary electrophoresis Methods 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000002946 cyanobenzyl group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 125000006285 dibromobenzyl group Chemical group 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 125000006286 dichlorobenzyl group Chemical group 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
- C25B3/29—Coupling reactions
Definitions
- the invention relates to a new process for the preparation of substituted Diaminodicarboxylic acid derivatives in high yield using Kolbe synthesis.
- Substituted diaminodicarboxylic acid derivatives are valuable intermediates in the synthesis of peptides.
- N-butyloxycarbonylglutamic acid ⁇ -benzyl ester is subjected to a Kolbe electrolysis.
- the anion of the protected amino acid is first oxidized and converted into a radical intermediate with elimination of CO 2 .
- This radical can now react with a solvent proton or in turn release a hydrogen atom with the formation of a double bond, while reaction with a second radical leads to the desired diaminodicarboxylic acid derivative.
- the decisive disadvantage of this method is a side reaction in which the reaction product reacts with the alcohol of the solvent and can thus be partially or completely transesterified. Of course, this process considerably reduces the yield of pure, isolated product, which is a maximum of 20% of theory, and the resulting product mixture is particularly difficult and expensive to clean.
- Diaminodicarboxylic acid derivatives can be found that prevent the formation of Avoid transesterification products.
- the invention therefore relates to a process for the preparation of substituted diaminodicarboxylic acid derivatives of the formula in which R 1 and R 2 each independently of one another are an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms or a radical means, where A is an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms or an optionally one or more or mixed benzyl radical or 9-fluorenylmethyl and R 3 substituted by halogen, -NO 2 , alkoxy or -CN straight-chain or branched alkyl radical having 1-4 C atoms, the chirality centers in the molecules being determined by the starting materials used and both L or both D or D, L or L, D can be configured and n is an integer of 2 -8 means by optionally mixed Kolbe synthesis, which is characterized in that a protected amino acid derivative of the formula in which R 1 and R 3 have the meaning given above
- R 1 and R 2 each represent an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms, for example methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl, t-butyl, pentyl or hexyl, which can optionally be halogenated one or more times.
- R 1 and R 2 can be a residue mean, where A is 9-fluorenylmethyl or an optionally mono- or polysubstituted or mixed by halogen, NO 2 , alkoxy or -CN substituted benzyl radical, for example a bromobenzyl, dibromobenzyl, chlorobenzyl, dichlorobenzyl, nitrobenzyl, methoxybenzyl or Cyanobenzyl residue.
- R 1 and R 2 each preferably represent a radical where A is a 9-fluorenylmethyl radical, an optionally substituted benzyl radical or a straight-chain or branched alkyl radical having 1-4 C atoms.
- the radical R 3 denotes a straight-chain or branched alkyl radical with 1-4 C atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, preferably methyl, ethyl or i-propyl.
- the chirality centers of the dicarboxylic acids are determined by the choice of the starting materials used. You can use either both D or both L or D, L or L, D, for example N'-R 1 -N '' - R 2 -2,7-D, L-2,7-diaminosuberinklare-di-R 3 -ester when using NR 1 -D-glutamic acid-R 3 ester and NR 2 -L-glutamic acid-R 3 ester.
- the amino acid derivatives of the formulas II and III are dissolved in a solvent R 4 OH or a heterocyclic solvent such as pyridine or dimethylformamide or acetonitrile or mixtures of such solvents, where R 4 has the meaning of R 3 , for example methyl, ethyl, n Propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl, ethyl or i-propyl.
- a base is added to the solution in the electrolysis cell, for example alkali metal in R 4 OH, for example sodium methoxide in methanol, or potassium ethoxide in ethanol.
- Electrolysis is then carried out on platinum mesh electrodes with cooling, the temperature preferably being kept at 18-25 ° C.
- the current in the electrolysis is about 5-15 A at a voltage of 60-120 V and is otherwise dependent on the geometry of the electrode used.
- the electrolysis process is ended as soon as no educt can be found in the electrolysis solution.
- the electrolysis solution is then optionally concentrated under low pressure, the residue is taken up in a suitable solvent, for example ethyl acetate, and this solution is washed successively with dilute acid, for example dilute hydrochloric acid, a saturated salt solution, for example a saturated sodium hydrogen carbonate solution, and saturated sodium chloride solution.
- dilute acid for example dilute hydrochloric acid
- a saturated salt solution for example a saturated sodium hydrogen carbonate solution
- saturated sodium chloride solution saturated sodium chloride solution.
- the solution is then dried with a suitable drying agent, for example sodium sulfate or magnesium sulfate, filtered and concentrated again, if appropriate under low pressure.
- the residue of the Kolbe synthesis was dissolved in 250 ml of ethyl acetate, first with dilute HCl solution (75 ml of HCl conc. Made up to 200 ml with H 2 O), then with 200 ml of NaHCO 3 sat. and finally with 200 ml of NaCl sat. washed until neutrality of the aqueous phase.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Electrochemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
Die Erfindung betrifft ein neues Verfahren zur Herstellung substituierter Diaminodicarbon-säurederivate in hoher Ausbeute mittels Kolbe-Synthese.The invention relates to a new process for the preparation of substituted Diaminodicarboxylic acid derivatives in high yield using Kolbe synthesis.
Substituierte Diaminodicarbonsäurederivate sind wertvolle Zwischenprodukte in der Synthese von Peptiden.Substituted diaminodicarboxylic acid derivatives are valuable intermediates in the synthesis of peptides.
In der bislang effektivsten Synthese wird beispielsweise N-t-butyloxycarbonylglutaminsäure-α-benzylester
einer Kolbe-Elektrolyse unterzogen.
Bei dieser im Basischen ablaufenden Reaktion wird das Anion der geschützten
Aminosäure zunächst oxidiert und unter CO2-Abspaltung in ein Radikal-Intermediate
umgewandelt. Dieses Radikal kann nun mit einem Solvens-Proton
reagieren, oder seinerseits unter Ausbildung einer Doppelbindung ein
Wasserstoffatom abgeben, während Reaktion mit einem zweiten Radikal zum
gewünschten Diaminodicarbonsäurederivat führt.
Der entscheidende Nachteil dieser Methode ist eine Nebenreaktion, bei der
das Reaktionsprodukt mit dem Alkohol des Lösungsmittels reagieren und so
teilweise oder vollständig umgeestert werden kann. Dieser Prozeß reduziert
natürlich die Ausbeute an reinem, isolierten Produkt beträchtlich, die maximal
20% der Theorie beträgt, auch ist das entstehende Produktgemisch nur
besonders schwierig und aufwendig zu reinigen.In the most effective synthesis to date, for example, N-butyloxycarbonylglutamic acid α-benzyl ester is subjected to a Kolbe electrolysis. In this basic reaction, the anion of the protected amino acid is first oxidized and converted into a radical intermediate with elimination of CO 2 . This radical can now react with a solvent proton or in turn release a hydrogen atom with the formation of a double bond, while reaction with a second radical leads to the desired diaminodicarboxylic acid derivative.
The decisive disadvantage of this method is a side reaction in which the reaction product reacts with the alcohol of the solvent and can thus be partially or completely transesterified. Of course, this process considerably reduces the yield of pure, isolated product, which is a maximum of 20% of theory, and the resulting product mixture is particularly difficult and expensive to clean.
Auf J. Org. Chem. 45, ss 3078 - 3080 (1980) wird auch hingewiesen.Attention is also drawn to J. Org. Chem. 45 , pp. 3078-3080 (1980).
Überraschenderweise konnte ein Verfahren zur Synthese von Diaminodicarbonsäurederivaten gefunden werden, das die Bildung von Umesterungsprodukten vermeidet. Surprisingly, a method for the synthesis of Diaminodicarboxylic acid derivatives can be found that prevent the formation of Avoid transesterification products.
Gegenstand der Erfindung ist daher ein Verfahren zur Herstellung
substituierter Diaminodicarbonsäurederivate der Formel
durch gegebenenfalls gemischte Kolbe-Synthese, das dadurch gekennzeichnet
ist, daß ein geschütztes Aminosäurederivat der Formel
in einem Lösungsmittel R4OH, wobei R4 die Bedeutung von R3 hat, oder einem
heterozyklischen oder aliphatischen, mindestens ein Heteroatom enthaltenden
Lösungsmittel oder Mischungen solcher Lösungsmittel gelöst wird und einer
Elektrolyse an Platinnetzelektroden unterworfen und das Produkt
gegebenenfalls mit LiOH hydrolisiert wird.The invention therefore relates to a process for the preparation of substituted diaminodicarboxylic acid derivatives of the formula
by optionally mixed Kolbe synthesis, which is characterized in that a protected amino acid derivative of the formula
in a solvent R 4 OH, where R 4 is R 3 , or a heterocyclic or aliphatic solvent containing at least one hetero atom or mixtures of such solvents is dissolved and subjected to electrolysis on platinum network electrodes and the product is optionally hydrolyzed with LiOH.
Der Vorteil dieses Verfahrens besteht einerseits in der hohen Ausbeute an reinem, isolierten Produkt von mindestens 34% der Theorie, andererseits kann durch den geringeren Anteil an Nebenprodukten der Reinigungsaufwand erheblich reduziert werden. Daher ist dieses Verfahren geeignet, die Herstellungskosten von Folgeprodukten, wie Peptiden und nicht natürlich vorkommende Aminosäuren enthaltenden Verbindungen, erheblich zu reduzieren.The advantage of this process is the high yield pure, isolated product of at least 34% of theory, on the other hand, can due to the lower proportion of by-products, the cleaning effort be significantly reduced. Therefore, this method is suitable Manufacturing costs of secondary products, such as peptides and not natural occurring compounds containing amino acids significantly to reduce.
In den Formeln I, II und III bedeuten R1 und R2 jeweils einen gegebenenfalls halogenierten geradkettigen, verzweigten oder zyklischen Alkylrest mit 1-10 C-Atomen, beispielseise Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-Butyl, t-Butyl, Pentyl- oder Hexylrest, der gegebenenfalls ein- oder mehrfach halogeniert sein kann.In the formulas I, II and III, R 1 and R 2 each represent an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms, for example methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl, t-butyl, pentyl or hexyl, which can optionally be halogenated one or more times.
Weiters können R1 und R2 einen Rest
Vorzugsweise bedeuten R1 und R2 jeweils einen Rest
Der Rest R3 bedeutet einen geradkettigen oder verzweigten Alkylrest mit 1-4 C-Atomen, beispielsweise Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-Butyl-, t-Butyl-, vorzugsweise Methyl, Ethyl oder i-Propyl.The radical R 3 denotes a straight-chain or branched alkyl radical with 1-4 C atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, preferably methyl, ethyl or i-propyl.
Die Chiralitätszentren der Dicarbonsäuren werden durch die Wahl der verwendeten Edukte bestimmt. Sie können entweder beide D oder beide L oder D,L bzw. L,D, beispielsweise N'-R1-N''-R2-2,7-D,L-2,7-diaminosuberinsäure-di-R3-ester bei Verwendung von N-R1-D-glutaminsäure-R3-ester und N-R2-L-glutaminsäure-R3-ester, konfiguriert sein.The chirality centers of the dicarboxylic acids are determined by the choice of the starting materials used. You can use either both D or both L or D, L or L, D, for example N'-R 1 -N '' - R 2 -2,7-D, L-2,7-diaminosuberinsäure-di-R 3 -ester when using NR 1 -D-glutamic acid-R 3 ester and NR 2 -L-glutamic acid-R 3 ester.
Die Aminosäurederivate der Formeln II und III werden in einem Lösungsmittel R4OH oder einem heterozyklischen Lösungsmittel wie beispielsweise Pyridin oder Dimethylformamid oder Acetonitril oder Mischungen solcher Lösungsmittel gelöst, wobei R4 die Bedeutung von R3 hat, also beispielsweise Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-Butyl- oder t-Butyl-, vorzugsweise Methyl, Ethyl oder i-Propyl bedeutet.. The amino acid derivatives of the formulas II and III are dissolved in a solvent R 4 OH or a heterocyclic solvent such as pyridine or dimethylformamide or acetonitrile or mixtures of such solvents, where R 4 has the meaning of R 3 , for example methyl, ethyl, n Propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl, ethyl or i-propyl.
In der Elektrolysezelle wird der Lösung eine Base zugefügt, beispielsweise
Alkalimetall in R4OH, etwa Natriummethoxid in Methanol, oder Kaliumethoxid in
Ethanol.
Anschließend wird an Platinnetzelektroden unter Kühlen elektrolysiert, wobei
die Temperatur vorzugsweise auf 18-25 °C gehalten wird. Die Stromstärke bei
der Elektrolyse beträgt etwa 5-15 A bei 60-120 V angelegter Spannung und ist
im übrigen abhängig von der Geometrie der verwendeten Elektrode.
Der Elektrolysevorgang wird beendet, sobald kein Edukt in der
Elektrolyselösung mehr festgestellt werden kann.
Die Elektrolyselösung wird anschließend gegebenenfalls unter niedrigem
Druck eingeengt, der Rückstand in einem geeigneten Lösungsmittel,
beispielsweise Ethylacetat aufgenommen und diese Lösung nacheinander mit
verdünnter Säure, beispielsweise verdünnter Salzsäure, einer gesättigten
Salzlösung, beispielsweise einer gesättigten Natriumhydrogencarbonatlösung,
und gesättigter Natriumchloridlösung gewaschen.
Die Lösung wird anschließend mit einem geeigneten Trocknungsmittel,
beispielsweise Natriumsulfat oder Magnesiumsulfat, getrocknet, filtriert und
erneut, gegebenenfalls unter niedrigem Druck, eingeengt.A base is added to the solution in the electrolysis cell, for example alkali metal in R 4 OH, for example sodium methoxide in methanol, or potassium ethoxide in ethanol.
Electrolysis is then carried out on platinum mesh electrodes with cooling, the temperature preferably being kept at 18-25 ° C. The current in the electrolysis is about 5-15 A at a voltage of 60-120 V and is otherwise dependent on the geometry of the electrode used.
The electrolysis process is ended as soon as no educt can be found in the electrolysis solution.
The electrolysis solution is then optionally concentrated under low pressure, the residue is taken up in a suitable solvent, for example ethyl acetate, and this solution is washed successively with dilute acid, for example dilute hydrochloric acid, a saturated salt solution, for example a saturated sodium hydrogen carbonate solution, and saturated sodium chloride solution.
The solution is then dried with a suitable drying agent, for example sodium sulfate or magnesium sulfate, filtered and concentrated again, if appropriate under low pressure.
Der Rückstand wird chromatographisch gereinigt, beispielsweise über Silicagel, was wegen des geringen Anteils an Nebenprodukten mit vergleichsweise geringem Aufwand möglich ist. Gegenüber einem früheren Verfahren, bei dem R3 und R4 nicht identisch waren, verläuft die Reaktion in einer Ausbeute von bis zu 35% d.Th. im Gegensatz zu früheren 10-15%. The residue is purified by chromatography, for example over silica gel, which is possible with comparatively little effort because of the small proportion of by-products. Compared to an earlier process in which R 3 and R 4 were not identical, the reaction proceeds in a yield of up to 35% of theory unlike previous 10-15%.
47,40 g (181 mmol) N-t-Butyloxycarbonylglutaminsäure-α-t-methylester wurden
in 240 ml MeOH und 80 ml Pyridin durch Umschwenken gelöst. Die
Reaktionslösung wurde in die Elektrolysezelle mit zylinderförmig angeordneten
Platinnetzelektroden transferiert. Es wurde mit MeOH nachgespült und die
Elektrolysezelle soweit mit MeOH aufgefüllt, daß beide Elektroden vollständig
eintauchten.
Nun wurden 0,8 ml NaOCH3 (30% in MeOH) zugegeben, und die
Reaktionslösung auf 15°C gekühlt. Die Reaktionstemperatur wurde durch
Temperaturregelung bzw. durch Regelung der Stromstärke bzw. -spannung (5-15
A, 60-120 V) zwischen +18°C und +24°C gehalten.
Der Reaktionsverlauf wurde mittels DC kontrolliert.
Nach vollständiger Reaktion wurde die Reaktionslösung bei 40 °C einrotiert.47.40 g (181 mmol) of Nt-butyloxycarbonylglutamic acid-α-t-methyl ester were dissolved in 240 ml of MeOH and 80 ml of pyridine by inverting. The reaction solution was transferred into the electrolytic cell with cylindrical platinum mesh electrodes. It was rinsed with MeOH and the electrolytic cell was filled with MeOH until both electrodes were completely immersed.
Now 0.8 ml NaOCH 3 (30% in MeOH) was added and the reaction solution was cooled to 15 ° C. The reaction temperature was kept between + 18 ° C and + 24 ° C by regulating the temperature or regulating the current or voltage (5-15 A, 60-120 V).
The course of the reaction was checked by TLC.
After the reaction was complete, the reaction solution was spun in at 40 ° C.
Der Rückstand der Kolbe-Synthese wurde in 250 ml Ethylacetat gelöst, zuerst mit verdünnter HCl-Lösung (75 ml HCl conc. mit H2O auf 200 ml aufgefüllt), dann mit 200 ml NaHCO3 ges. und zuletzt mit je 200 ml NaCl ges. bis zur Neutralität der wäßrigen Phase gewaschen.The residue of the Kolbe synthesis was dissolved in 250 ml of ethyl acetate, first with dilute HCl solution (75 ml of HCl conc. Made up to 200 ml with H 2 O), then with 200 ml of NaHCO 3 sat. and finally with 200 ml of NaCl sat. washed until neutrality of the aqueous phase.
Die organische Phase wurde mit Na2SO4 getrocknet, abfiltriert, und eingedampft. Eindampfrückstand: 37,93 g.The organic phase was dried with Na 2 SO 4 , filtered off and evaporated. Evaporation residue: 37.93 g.
Der Eindampfrückstand wurde über Kieselgel filtriert und anschließend mittels Säulenchromatographie aufgetrennt.The evaporation residue was filtered through silica gel and then by means of Column chromatography separated.
Die Produkt enthaltenden Fraktionen wurden konzentriert und aus dem öligen Rückstand (24,08 g) wurden aus 100 ml Petrolether: Cyclohexan = 3: 1 13,69 g farblose Kristalle erhalten.The product-containing fractions were concentrated and extracted from the oily Residue (24.08 g) was extracted from 100 ml of petroleum ether: cyclohexane = 3: 1 Obtained 13.69 g of colorless crystals.
Ausbeute: 13,69 g des reinen Bis-N',N''-Benzyloxycarbonyl-2,7-diaminosuberinsäuredimethylester
(35% d.Th.), Fp.65-68 C.
13C(CDCl3, 100MHz): 24.86(2CH2), 28.30((CH3)3C), 32.53(2CH2), 52.17(2
OMe), 53.29, (2CH), 79.87(2(CH3)3 C), 155.31 (2carbamat-CO), 173.20(2ester-CO). Yield: 13.69 g of the pure bis-N ', N''- benzyloxycarbonyl-2,7-diaminosuberic acid dimethyl ester (35% of theory), mp 65-68 C.
13 C (CDCl 3 , 100MHz): 24.86 (2CH 2 ), 28.30 (( C H 3 ) 3 C), 32.53 (2CH 2 ), 52.17 (2 OMe), 53.29, (2CH), 79.87 (2 (CH 3 ) 3 C ), 155.31 (2carbamate-CO), 173.20 (2ester-CO).
1,5 g (1,16 mmol) Bis-N',N''-Benzyloxycarbonyl-2,7-diaminosuberinsäuredimethylester wurden in einer Lösung aus 1,5 ml Wasser und 3 ml MeOH gelöst. Zu dieser Lösung wurden 1,45 ml (2,90 mmol, 1,25 Äquivalente) einer 2N LiOH-Lösung in Wasser gegeben. Durch vorsichtige Zugabe von etwa 1 ml MeOH entstand aus der leicht trüben eine klare Lösung. Die Reaktionslösung wurde bei Raumtemperatur gerührt und anschließend am Rotavapor auf 3 ml konzentriert und der pH-Wert der Lösung mit 5% KHSO4-Lösung auf 2-3 gestellt. Die saure Lösung wurde mit Chloroform extrahiert, die organische Phase mit Na2SO4 getrocknet, filtriert und konzentriert. Es wurde 0,555 g an Rohprodukt erhalten, das aus Acetonitril umkristallisiert wurde.1.5 g (1.16 mmol) of bis-N ', N''- benzyloxycarbonyl-2,7-diaminosuberinsäuredimimylester were dissolved in a solution of 1.5 ml of water and 3 ml of MeOH. 1.45 ml (2.90 mmol, 1.25 equivalents) of a 2N LiOH solution in water were added to this solution. By carefully adding about 1 ml of MeOH, a clear solution resulted from the slightly cloudy. The reaction solution was stirred at room temperature and then concentrated to 3 ml on a Rotavapor and the pH of the solution was adjusted to 2-3 with 5% KHSO 4 solution. The acidic solution was extracted with chloroform, the organic phase dried with Na 2 SO 4 , filtered and concentrated. 0.555 g of crude product was obtained, which was recrystallized from acetonitrile.
Ausbeute: 0,324 g (80%). Untersuchung mit chiraler Kapillarelektrophoese ergibt, daß keine Racemisierung nachweisbar ist. Yield: 0.324 g (80%). Examination with chiral capillary electrophoresis shows that no racemization is detectable.
Analog zu den Beispielen 1 und 2 wurden folgende Verbindungen synthetisiert:
Di-Boc-D,D-SUB-di-OMe
Ausbeute: 1.15g, (35% d. Th.), Schmp.:42-47°C.
1H NMR (400 MHz, CDCl3) δ 4.99(s, 2 H, 2 NH), 4.27(s, 2 H, 2 CH), 3.73(s, 6
H, 2 OMe), 1.76 und 1.60 (m, 2 H), 1.44(s, 18 H), 1.35(m, 4 H).
13C NMR (100 MHz, CDCl3) δ 173.2, 155.3, 79.9, 53.3, 52.2, 32.5, 28.3, 24.9.The following compounds were synthesized analogously to Examples 1 and 2:
Di-Boc-D, D-SUB-di-OMe
Yield: 1.15 g, (35% of theory), mp: 42-47 ° C.
1 H NMR (400 MHz, CDCl 3 ) δ 4.99 (s, 2 H, 2 NH), 4.27 (s, 2 H, 2 CH), 3.73 (s, 6 H, 2 OMe), 1.76 and 1.60 (m, 2 H), 1.44 (s, 18 H), 1.35 (m, 4 H).
13 C NMR (100 MHz, CDCl 3 ) δ 173.2, 155.3, 79.9, 53.3, 52.2, 32.5, 28.3, 24.9.
Ausbeute: 0.37g (79% d. Th.). Schmp.: 152-154°C.
1H NMR (400 MHz, MeOH-d3) δ 4.12(s, 2 H, 2 CH), 1.82 und 1.70(m, 2 H),
1.48(s, 18 H, 2 C(CH3)3), 1.45(m, 4 H, 2 CH2).
13C NMR (100 MHz, DMSO-d6) δ 176.5, 158.1, 80.8, 55.1, 33.0, 29.0, 26.8.Yield: 0.37 g (79% of theory). Mp: 152-154 ° C.
1 H NMR (400 MHz, MeOH-d 3 ) δ 4.12 (s, 2 H, 2 CH), 1.82 and 1.70 (m, 2 H), 1.48 (s, 18 H, 2 C (CH 3 ) 3 ), 1:45 (m, 4 H, 2 CH2).
13 C NMR (100 MHz, DMSO-d 6 ) δ 176.5, 158.1, 80.8, 55.1, 33.0, 29.0, 26.8.
Ausbeute: 7.29g HN-60204, (33.6% d. Th.), leicht gelbliches Öl.
1H NMR (400 MHz, CDCl3) δ 5.00(br s,1 H, NH), 4.26(br s, 1 H, CH), 4.19(q, 2
H, OCH 2CH3), 2.46(m, 2 H), 1.78 und 1.60(m, 2 H), 1.44(s, 18 H), 1.35(m, 4
H), 1.28(t, 3 H, OCH2CH3 ).
13C NMR (100 MHz, CDCl3) δ 172.4, 155.0, 79.4, 60.9, 53.1, 32.3, 28.0, 24.6,
143.9.Yield: 7.29g HN-60204, (33.6% of theory), slightly yellowish oil.
1 H NMR (400 MHz, CDCl 3 ) δ 5.00 (br s, 1 H, NH), 4.26 (br s, 1 H, CH), 4.19 (q, 2 H, OC H 2 CH 3 ), 2.46 (m , 2 H), 1.78 and 1.60 (m, 2 H), 1.44 (s, 18 H), 1.35 (m, 4 H), 1.28 (t, 3 H, OCH 2 C H 3 ).
13 C NMR (100 MHz, CDCl 3 ) δ 172.4, 155.0, 79.4, 60.9, 53.1, 32.3, 28.0, 24.6, 143.9.
Ausbeute: 3.7g (84%), Schmp.: 150-153°C.
Die oben verwendeten Abkürzungen bedeuten:
- Boc:
- t-Butyloxycarbonyl
- SUB:
- 2,7-Diaminosuberinsäure
- Me:
- Methyl
- Et:
- Ethyl
- Boc:
- t-butyloxycarbonyl
- SUB:
- 2,7-diaminosuberic acid
- Me:
- methyl
- Et:
- Ethyl
Claims (2)
- Process for the preparation of substituted diaminodicarboxylic acid derivatives of the formulain which R1 and R2 in each case independently of one another are an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms or a radical
wherein A is an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C atoms or a benzyl radical which is optionally mono- or polysubstituted by identical or different halogen, -NO2, alkoxy or -CN substituents, or is 9-fluorenylmethyl
and R3 is a straight-chain or branched alkyl radical having 1-4 C atoms, the chirality centres in the molecules being determined by the starting materials used and it being possible for both to be in the L or both to be in the D or D,L or L,D configuration, and n is an integer from 2 to 8,
by optionally mixed Kolbe synthesis, which is characterized in that a protected amino acid derivative of the formulain which R1 and R3 have the abovementioned meaning and k is an integer, is dissolved with a protected amino acid derivative of the formula
in which R1 and R3 have the abovementioned meaning and l is an integer, wherein k and l together give the number n,
in a solvent R4OH, wherein R4 has the meaning of R3, or a heterocyclic or aliphatic solvent containing at least one heteroatom or mixtures of such solvents, the solution is subjected to electrolysis on platinum gauze electrodes and, if appropriate, the product is hydrolysed with LiOH. - Process for the preparation of those substituted diaminodicarboxylic acid derivatives of the formula I according to claim 1, in which R1 and R2 are each a radicalwherein A is an optionally halogenated straight-chain, branched or cyclic alkyl radical having 1-10 C-atoms or an optionally substituted benzyl radical or 9-fluorenylmethyl and R3 is a straight-chain or branched alkyl radical having 1-4 C atoms, the reaction taking place in a solvent mixture of R4OH, wherein R3 and R4 are identical, and pyridine, dimethylformamide or acetonitrile.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT1348/94 | 1994-07-08 | ||
| AT0134894A ATA134894A (en) | 1994-07-08 | 1994-07-08 | METHOD FOR PRODUCING SUBSTITUTED DIAMINODICARBONIC ACID DERIVATIVES |
| AT134894 | 1994-07-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0691422A1 EP0691422A1 (en) | 1996-01-10 |
| EP0691422B1 true EP0691422B1 (en) | 1999-11-03 |
Family
ID=3511955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP95109588A Expired - Lifetime EP0691422B1 (en) | 1994-07-08 | 1995-06-21 | Process for the preparation of substituted diaminodicarboxylic acid derivatives |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5643438A (en) |
| EP (1) | EP0691422B1 (en) |
| JP (1) | JPH0899942A (en) |
| AT (2) | ATA134894A (en) |
| AU (1) | AU700928B2 (en) |
| CA (1) | CA2153449A1 (en) |
| DE (1) | DE59507161D1 (en) |
| ES (1) | ES2140583T3 (en) |
| GR (1) | GR3032383T3 (en) |
| HU (1) | HU218876B (en) |
| NO (1) | NO308295B1 (en) |
| ZA (1) | ZA955675B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6852287B2 (en) * | 2001-09-12 | 2005-02-08 | Handylab, Inc. | Microfluidic devices having a reduced number of input and output connections |
| WO2018185084A1 (en) * | 2017-04-03 | 2018-10-11 | Evonik Degussa Gmbh | Method of producing vinylglycine |
| JP7064594B2 (en) * | 2017-12-21 | 2022-05-10 | パフォーマンス・ポリアミデス，エスアエス | Method for preparing primary diamine by Kolbe electrolysis coupling reaction |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2248562A1 (en) * | 1972-10-04 | 1974-04-11 | Basf Ag | PROCESS FOR THE PRODUCTION OF DICARBONIC ACID DIESTERS BY ELECTROCHEMICAL CONDENSATION OF DICARBONIC MONOESTERS |
| US5364851A (en) * | 1991-06-14 | 1994-11-15 | International Synthecon, Llc | Conformationally restricted biologically active peptides, methods for their production and uses thereof |
-
1994
- 1994-07-08 AT AT0134894A patent/ATA134894A/en not_active IP Right Cessation
-
1995
- 1995-06-05 US US08/463,267 patent/US5643438A/en not_active Expired - Fee Related
- 1995-06-21 ES ES95109588T patent/ES2140583T3/en not_active Expired - Lifetime
- 1995-06-21 EP EP95109588A patent/EP0691422B1/en not_active Expired - Lifetime
- 1995-06-21 AT AT95109588T patent/ATE186337T1/en not_active IP Right Cessation
- 1995-06-21 DE DE59507161T patent/DE59507161D1/en not_active Expired - Fee Related
- 1995-07-03 AU AU23394/95A patent/AU700928B2/en not_active Ceased
- 1995-07-06 JP JP7171090A patent/JPH0899942A/en not_active Withdrawn
- 1995-07-07 HU HU9502090A patent/HU218876B/en not_active IP Right Cessation
- 1995-07-07 ZA ZA955675A patent/ZA955675B/en unknown
- 1995-07-07 NO NO952719A patent/NO308295B1/en not_active IP Right Cessation
- 1995-07-07 CA CA002153449A patent/CA2153449A1/en not_active Abandoned
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2000
- 2000-01-14 GR GR20000400082T patent/GR3032383T3/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE59507161D1 (en) | 1999-12-09 |
| AU700928B2 (en) | 1999-01-14 |
| ZA955675B (en) | 1996-02-20 |
| US5643438A (en) | 1997-07-01 |
| GR3032383T3 (en) | 2000-04-27 |
| ES2140583T3 (en) | 2000-03-01 |
| AU2339495A (en) | 1996-01-18 |
| HUT73154A (en) | 1996-06-28 |
| NO952719D0 (en) | 1995-07-07 |
| JPH0899942A (en) | 1996-04-16 |
| HU9502090D0 (en) | 1995-09-28 |
| HU218876B (en) | 2000-12-28 |
| ATA134894A (en) | 1997-12-15 |
| EP0691422A1 (en) | 1996-01-10 |
| CA2153449A1 (en) | 1996-01-09 |
| NO952719L (en) | 1996-01-09 |
| NO308295B1 (en) | 2000-08-28 |
| ATE186337T1 (en) | 1999-11-15 |
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